The present invention is a method of tissue engineering, and specifically relates to administration of angiogenic factors directly to diabetic wound ulcers, in an effective amount for a sustained period of time effective to promote closure.
Among the 16 million diabetic patients (diagnosed and undiagnosed) in the United States, an estimated 1200 amputations are performed each week (Pecoraro, et al., Diabetes Care. 1990; 13:213-521); 84% of which are preceded by a foot ulcer. Limb amputation in diabetics is associated with an increased risk for further amputation, with a five-year mortality rate of 39 to 68% (Reiber et al. Diabetes in America. Washington, D.C.; U.S. Government Printing Office, 1995:409-428). The direct costs of a lower extremity amputation range from $20,000 to $60,000. When failed vascular reconstruction, rehabilitation, and lost productivity within society are considered, these costs greatly exceed financial analysis. The grave consequences, pain, and suffering endured by patients with diabetic foot ulcers mandate determination of the best combination of therapies to prevent progression and, consequent occurrence of these complications.
In addition to amputation, the need to have accelerated healing in diabetic patients with foot ulcers is accentuated because these patients have impaired immunity (Geerlings et al. FEMS Immunol Med Microbiol. 1999; 3-4:259-265; Feige et al., EXS. 1996; 77:359-373; Bessman et al., J Diabetes Complications. 1992; 4:258-262; Abraham, et al., J Dermatol. 1990; 7440-447; Loots et al., J Invest Dermatol. 1998; 5:850-857; Brown et al., J Surg Research 1994; 56:562-570; Greenhalgh et al., Am J Pathol 1990; 1361235-1246). Since unhealed open wounds are portals for systemic infection, they can have particularly devastating effects for the diabetic patient.
It is well known that diabetic patients are predisposed to ulceration. This predisposition has multiple etiologies, including endothelial cell dysfunction, accelerated atherosclerosis, and peripheral neuropathy, which relate to the endothelium and contribute to deficits in healing. One of the most central etiologies for this predisposition is the reduced angiogenic response in the diabetic patient.
Recently, local use of growth factors has been shown to be promising for the treatment of diabetic ulcers. Two new agents have been FDA approved for the treatment of diabetic foot ulcers. The first, platelet derived growth factor (PDGF-BB), has shown efficacy. The second, human skin equivalent, has also shown efficacy in the treatment of diabetic foot ulcers. However, despite their successes, there remain several significant problems with these therapies: neither has demonstrated efficacy in ischemic diabetic foot ulcers, and both have a minimum failure rate of 45% in well vascularized limbs. Although this is better than the failure rate of standard therapies (i.e., off-loading and saline dressing), the number of amputations and non-healed diabetic foot ulcers remains excessive. Although both of these therapies have also demonstrated that local therapy is clinically effective in the treatment of diabetic foot ulcers, more therapies are clearly needed.
Therefore, it is an object of the present invention to provide a method and means to provide increased blood flow to diabetic ulcers, and thereby promote wound closure.